A program of studies in clinical psychopharmacology has been proposed. Several areas will be looked at: a) Utility of plasma concentrations and kinetics of psychotherapeutic drugs. The initial study will focus on possible differences in kinetics and metabolism of drugs between Japanese and persons in the U.S. Other studies will be added as deemed to be timely. b) Human model of anxiety for testing antianxiety drugs. Anxiety produced by the alpha-2 adrenoreceptor antagonist given yohimbine orally to man will be studied, looking at intersubject variability in response, symptoms and signs, and plasma concentrations of norepinephrine and urinary excretion of MHPG. c) Novel approaches to treating schizophrenics. A controlled study of the possible utility of high doses of thiothixene for treatment-resistant patients is underway, also measuring plasma concentrations of the drug. Evidence of dopaminergic supersensitivity in treatment-resistant patients will be studied by measuring serum prolactin levels, as well as by assessing tardive dyskinesia, and relating both evidences to serum neuroleptic levels as by assessing tardive dyskinesia, and relating both evidences to serum neuroleptic levels. An atypical benzodiazepines will be studied in a controlled fashion for its effects on "negative" symptoms of schizophrenia, following some preliminary work indicating this to be the case. A limbic epilepsy model will look at factors that may induce dopamine receptor binding sites in animals with such foci. The question of abnormal lymphocytes in schizophrenia will be re-examined using both morphological and serological techniques. d) Miscellaneous studies. The parameters of "therapeutic-dose" dependence on benzodiazepines will be investigated in small animals.